ABSTRACT During development, tightly regulated mechanisms establish the proper balance between excitatory (E) and inhibitory (I) synaptic inputs made onto each neuronal cell type. Several neurodevelopmental disorders are thought to have emerged from E/I synaptic imbalance including autism spectrum disorders (ASD) and schizophrenia. However, the mechanisms coordinating excitatory and inhibitory synaptic development are still poorly understood. We recently discovered that SRGAP2 is a postsynaptic protein playing key roles in vivo in promoting the rate of excitatory and inhibitory synapses maturation and limiting the density of both types of synapses made onto pyramidal neurons in the developing cortex. In the previous funding period, we first made significant progress in dissecting the molecular mechanisms underlying SRGAP2 function at both excitatory and inhibitory synapses, discovering that its ability to promote excitatory synaptic maturation requires its ability to bind to Homer1, a key postsynaptic scaffolding protein at excitatory synapses, but promotes inhibitory synapse maturation through its ability to bind to Gephyrin, a key scaffolding protein at inhibitory synapses. Finally, SRGAP2 regulates the density of excitatory and inhibitory synapses made onto a pyramidal neuron through its Rac1-GAP activity. Secondly, we and others discovered that SRGAP2 has undergone several partial gene duplications specifically in the human lineage. Only one of these gene duplications, called SRGAP2C (the ancestral copy of the human gene was renamed SRGAP2A) has been fixed in the human population and is expressed in the developing human brain. We discovered that SRGAP2C binds to and inhibits the functions of SRGAP2A during synaptic development. When human-specific SRGAP2C is expressed in mouse cortical pyramidal neurons in vivo, it induces significant delay (neoteny) of synaptic maturation and significant increase in both excitatory and inhibitory synapse density. The present proposal constitutes a comprehensive, multi-disciplinary approach to address some fundamental questions raised by our results from the previous funding period: Is SRGAP2A and its human-specific paralogs only involved in synaptic development or is it also regulating synaptic plasticity? What types of functional properties emerge in mouse cortical circuits following humanization of SRGAP2C expression? What are the consequences of structural changes induced by SRGAP2A and its human- specific paralog SRGAP2C on cortical circuit organization and function as well as behavioral performance? Our aim is to test if human-specific gene duplication of SRGAP2A that led to the emergence of SRGAP2C represented an evolutionary relevant substrate for the emergence of new functional properties in cortical circuits. This project will tackle with unprecedented relevance the relationship between genes, neural circuits and behavior in a framework of human cortical development and evolution.